Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor Type-1 (PAI-1)

ABSTRACT

This invention provides PAI-1 inhibiting compounds of Formula I:  
                 
 
     wherein: R 1 , R 2 , R 3 , and R 4  are each H, alkyl, , alkanoyl, halo, OH, aryl optionally substituted with R 8 , perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, perfluoroalkoxy; R 5  is H, alkyl, perfluoroalkyl, aryl optionally substituted with R 8 , alkanoyl, aroyl optionally substituted with R 8 ; R 6  is H, alkyl, alkylaryl, benzyl optionally substituted with R 8 , alkanoyl, aroyl optionally substituted with R 8 ; R 7  is H, alkyl, alkylaryl, aryl optionally substituted with R 8 ; n is 0-6; A is COOH, or an acid mimic such as tetraazole, SO 3 H, PO 3 H 2 , tetronic acid, etc.; R 8  is H, alkyl, cycloalkyl, alkanoyl, halo, OH, perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, perfluoroalkoxy; or a pharmaceutically acceptable salt thereof; as well as pharmaceutical compositions and methods of treatment using these compounds.

[0001] This invention relates to the composition and utility ofsubstituted naphthyl indole derivatives as inhibitors of plasminogenactivator inhibitor-1 (PAI-1) and as therapeutic compositions fortreating conditions resulting from fibrinolytic disorders such as deepvein thrombosis and coronary heart disease, and pulmonary fibrosis.

BACKGROUND OF THE INVENTION

[0002] Plasminogen activator inhibitor-1 (PAI-1) is a major regulatorycomponent of the plasminogen-plasmin system. PAI-1 is the principalphysiologic inhibitor of both tissue type plasminogen activator (tPA)and urokinase type plasminogen activator (uPA). Elevated plasma levelsof PAI-1 have been associated with thrombotic events as indicated byanimal experiments (Krishnamurti, Blood, 69, 798 (1987); Reilly,Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal ofClinical Investigation, 92, 2756 (1993)) and clinical studies (Rocha,Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis 24, 243 (1994)). Antibodyneutralization of PAI-1 activity resulted in promotion of endogenousthrombolysis and reperfusion (Biemond, Circulation, 91, 1175 (1995);Levi, Circulation 85, 305, (1992)). Elevated levels of PAI-1 have alsobeen implicated in diseases of women such as polycystic ovary syndrome(Nordt, Journal of clinical Endocrinology and Metabolism, 85, 4, 1563(2000)) and bone loss induced by estrogen deficiency (Daci, Journal ofBone and Mineral Research, 15, 8, 1510 (2000)). Accordingly, agents thatinhibit PAI-1 would be of utility in treating conditions originatingfrom fibrinolytic disorder such as deep vein thrombosis, coronary heartdisease, pulmonary embolism, polycystic ovary syndrome, etc.

[0003] WO 98/08818 discloses substituted indoles and benzimidazoles ofFormulas I, II, & III which are chemical inhibitors of variousphospholipase enzymes (such as PLA₂) useful in the treatment ofinflammation.

[0004] WO 96/21656 discloses compounds of Formula I which are useful fortreating or preventing obesity, breast cancer, osteoporosis,endometriosis, cardiovascular disease and prostatic disease.

[0005] In addition, the utilities of the current invention aredifferent.

[0006] EP 0 655 439 (Eli Lilly and Company) relates to 5,6 fused ringbicyclic compounds inclusive of indoles, benzofurans, andbenzothiophenes corresponding to the general Formula I as plateletaggregation inhibitors.

[0007] WO 95/10513 (Pfizer, Inc.) discloses substituted indoles,benzofurans, and benzthiophenes of Formula I as estrogen agonists whichare useful for treating syndromes and diseases caused by estrogendeficiency.

[0008] WO 94/26738 and EP 0 512 570 (Fujisawa Pharmaceutical Co., Ltd.)disclose the preparation of substituted indoles, benzofurans, andbenzthiophenes (Formula I) which possess an inhibitory activity againstACAT (cholesterol acyltransferase enzyme) and are useful for theprevention and/or treatment of hypercholesterolemia, hyperlipidemia,atherosclerosis or diseases caused thereby.

[0009] U.S. Pat. No. 5,151,435 discloses substitutedimidazolo/benzimidazolo-indoles and dihydroindoles of Formula I whichare useful as angiotensin II antagonists in the treatment ofhypertension.

[0010] EP 0 416 609 discloses indole-, benzofuran-, andbenzothiophene-containing lipoxygenase-inhibiting compounds (Formula I)as well as pro-drugs of these compounds having metabolically cleavablegroups.

DESCRIPTION OF THE INVENTION

[0011] This invention comprises compounds of Formula I:

[0012] wherein:

[0013] R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of1-3 carbons, cycloalkyl of 3-5 carbon atoms, —CH₂-cycloalkyl of 3-5carbon atoms, alkanoyl of 1-3 carbons, halogen, hydroxy, aryl optionallysubstituted with from 1 to 3 groups selected from R₈, perfluoroalkyl of1-3 carbons, alkoxy of 1-3 carbons, amino, alkylamino of 1-3 carbons,dialkylamino of 1-3 carbons, perfluoroalkoxy of 1-3 carbons;

[0014] R₅ is hydrogen, alkyl of 1-6 carbons, perfluoroalkyl of 1-6carbons, aryl substituted with R₈, alkanoyl of 1-6 carbons, aroyloptionally substituted with from 1 to 3 groups selected from R₈;

[0015] R₆ is hydrogen, alkyl of 1-6 carbons, alkylaryl, benzylsubstituted with R₈, alkanoyl of 1-6 carbons, aroyl optionallysubstituted with from 1 to 3 groups selected from R₈;

[0016] R₇ is hydrogen, alkyl of 1-6 carbons, alkylaryl, aryl optionallysubstituted with from 1 to 3 groups selected from R₈;

[0017] n is an integer of 0-6;

[0018] A is COOH or an acid mimic such as tetraazole, SO₃H, PO₃H₂,tetronic acid, etc.;

[0019] R₈ is hydrogen, alkyl of 1-3 carbons, cycloalkyl of 3-5 carbons,—CH₂-cycloalkyl of 3-5 carbon atoms, alkanoyl of 1-3 carbons, halogen,hydroxy, perfluoroalkyl of 1-3 carbons, alkoxy of 1-3 carbons, amino,alkylamino of 1-3 carbons, dialkylamino of 1-3 carbons, perfluoroalkoxyof 1-3 carbons;

[0020] or a pharmaceutically acceptable salt or ester form thereof.

[0021] As used herein, alkyl includes both straight and branched alkylmoieties and halogen includes bromine, chlorine, fluorine, and iodine.

[0022] Ester forms of the compounds of this invention include thepharmaceutically acceptable ester forms known in the art for the acidgroups of Formula I, above. These esters include straight chain alkylesters having from 1 to 6 carbon atoms or branched chain alkyl groupscontaining 3 or 6 carbon atoms, including methyl, ethyl, propyl, butyl,2-methylpropyl and 1,1-dimethylethyl esters. Other non-limiting examplesof esters useful with this invention include those wherein A is acarboxylic acid and the ester form has the formula —COOR₉ wherein R₉ isselected from the formulae:

[0023] wherein R₉, R₁₀, R₁₁ and R₁₂ are independently selected fromhydrogen, alkyl of from 1 to 10 carbon atoms, aryl of 6 to 12 carbonatoms, arylalkyl of from 6 to 12 carbon atoms; heteroaryl oralkylheteroaryl wherein the heteroaryl ring is bound by an alkyl chainof from 1 to 6 carbon atoms.

[0024] Among the preferred ester forms of the compounds herein includebut not limited to C₁-C₆ alkyl esters, C₃-C₆ branched alkyl esters,benzyl esters, etc.

[0025] Acid mimic or mimetics which are included in the acidic groups ofthis invention, as noted in the definition of A, above, particularlyinclude the pharmaceutically useful carboxylic acid mimics or mimeticsknown in the art, such as those described in R. Silverman, The OrganicChemistry of Drug Design and Drug Action, Academic Press (1992), thecontents of which are incorporated herein by reference. Non-limitingexamples of these acid mimics include such as tetrazole, SO₃H, PO₃H₂,tetronic acid, etc., or groups having the formulae:

[0026] wherein R₁₃ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl,—CH₂—(C₃-C₆ cycloalkyl), C₃-C₆ cycloalkenyl, —CH₂—(C₃-C₆ cycloalkenyl),optionally substituted aryl or heteroaryl groups or optionallysubstituted —C₁-C₆ alkyl-aryl or —C₁-C₆ alkyl-heteroaryl, with the aryland heteroaryl groups and their optional substitution as defined herein.

[0027] As used herein, “aryl” refers to an unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryl groups include phenyl, naphthyl and the like.As used herein, “heteroaryl” refers to a monocyclic or bicyclic aromaticgroup of from 1 to carbon atoms and 1 to 4 heteroatoms selected fromoxygen, nitrogen and sulfur within at least one ring (if there is morethan one ring). Such heteroaryl groups can have a single ring, such aspyridyl, pyrrolyl or furyl groups, or multiple condensed rings, such asindolyl, indolizinyl, benzofuranyl or benzothienyl groups. Preferredheteroaryls include pyridyl, pyrrolyl and furyl. It will be understoodthat the definitions of aryl and heteroaryl also refer to those portionsof any aroyl or heteroaroyl groups described herein.

[0028] Unless otherwise limited by the definition for the aryl orheteroaryl groups herein, such groups can optionally be substituted withfrom 1 to 5 substituents selected from the group consisting of acyloxy,hydroxy, acyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms,substituted alkyl, substituted alkoxy, substituted alkenyl, substitutedalkynyl, amino, amino substituted by one or two alkyl groups of from 1to 6 carbon atoms, aminoacyl, acylamino, azido, cyano, halo, nitro,thioalkoxy of from 1 to 6 carbon atoms, substituted thioalkoxy of from 1to 6 carbon atoms, and trihalomethyl. Substituents on the alkyl,alkenyl, alkynyl, thioalkoxy and alkoxy groups mentioned above includehalogens, CN, OH, and amino groups. Preferred substituents on the arylgroups herein include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl,and thioalkoxy.

[0029] Pharmaceutically acceptable salts of compounds of this inventioncontaining a basic group, such as amino or alkylamino groups, can beformed from organic and inorganic acids, for example, acetic, propionic,lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic,malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric,sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.Salts may also be formed from organic and inorganic bases, preferablyalkali metal salts, for example, sodium, lithium, or potassium.

[0030] Other useful salt forms of these compounds include those formedwith pharmaceutically acceptable inorganic and organic bases known inthe art. Salt forms prepared using inorganic bases include hydroxides,carbonates or bicarbonates of the therapeutically acceptable alkalimetals or alkaline earth methals, such as sodium potassium, magnesium,calcium and the like. Acceptable organic bases include amines, such asbenzylzmine, mono-, di- and trialkylamines, preferably those havingalkyl groups of from 1 to 6 carbon atoms, more preferably 1 to 3 carbonatoms, such as methylamine, dimethylamine, trimethylamine, ethylamine,diethylamine, triethylamine, mono-, di-, and triethanolamine. Alsouseful are alkylene diamines containing up to 6 carbon atoms, such ashexamethylenediamine; cyclic saturated or unsaturated bases containingup to 6 carbon atoms, including pyrrolidine, peperidine, morpholine,piperazine and their N-alkyl and N-hydroxyalkyl derivatives, such asN-methyl-morpholine and N-(2-hyroxyethyl)-piperidine, or pyridine.Quaternary salts may also be formed, such as tetralkyl forms, such astetramethyl forms, alkyl-alkanol forms, such as methyl-triethanol ortrimethyl-monoethanol forms, and cyclic ammonium salt forms, such asN-methylpyridinium, N-methyl-N-(2-hydroxyethyl)-morpholinium,N,N-di-methylmorpholinium, N-mehtyl-N-(2-hydroxyethyl)-morpholinium, orN,N-dimethyl-piperidinium salt forms. These salt forms may be preparedusing the acidic compound(s) of Formula I and procedures known in theart.

[0031] The compounds of this invention may contain an asymmetric carbonatom or sulfoxide moiety and some of the compounds of this invention maycontain one or more asymmetric centers and may thus give rise to opticalisomers and diastereomers. While shown without respect tostereochemistry in Formula I, the present invention includes suchoptical isomers and diastereomers; as well as the racemic and resolved,enantiomerically pure R and S stereoisomers; as well as other mixturesof the R and S stereoisomers and pharmaceutically acceptable saltsthereof.

[0032] The compounds of the present invention are inhibitors of theserine protease inhibitor PAI-1, and are therefore useful in thetreatment or prophylaxis of those processes which involve the productionand/or action of PAI-1. Thus, the compounds of the invention are usefulin the treatment or prevention of noninsulin dependent diabetes mellitusand cardiovascular disease caused by such condition, and prevention ofthrombotic events associated with coronary artery and cerebrovasculardisease. These compounds are also useful for inhibiting the diseaseprocess involving the thrombotic and prothrombotic states which include,but are not limited to, formation of atherosclerotic plaques, venous andarterial thrombosis, myocardial ischemia, atrial fibrillation, deep veinthrombosis, coagulation syndromes, pulmonary thrombosis, cerebralthrombosis, thromboembolic complications of surgery (such as jointreplacement), and peripheral arterial occlusion. These compounds arealso useful in treating stroke associated with or resulting from atrialfibrillation.

[0033] The compounds of the invention may also be used in the treatmentof diseases associated with extracellular matrix accumulation,including, but not limited to, renal fibrosis, chronic obstructivepulmonary disease, polycystic ovary syndrome, restenosis, renovasculardisease and organ transplant rejection.

[0034] The compounds of the invention may also be used in the treatmentof malignancies, and diseases associated with neoangiogenesis (such asdiabetic retinopathy).

[0035] The compounds in the invention may also be used in conjunctionwith and following processes or procedures involving maintaining bloodvessel patency, including vascular surgery, vascular graft and stentpatency, organ, tissue and cell implantation and transplantation.

[0036] The compounds of the invention may also be used in the treatmentof Alzheimer's disease. This method may also be characterized as theinhibition of plasminogen activator by PAI-1 in a mammal, particularly ahuman, experiencing or subject to Alzhemier's disease. This method mayalso be characterized as a method of increasing or normalizing levels ofplasmin concentration in a mammal, particularly those experiencing orsubject to Alzheimer's disease.

[0037] The compounds of the invention may be used for the treatment ofmyelofibrosis with myeloid metaplasia by regulating stromal cellhyperplasia and increases in extracellular matrix proteins.

[0038] The compounds of the invention may also be used in conjunctionwith protease inhibitor-containing highly active antiretroviral therapy(HAART) for the treatment of diseases which orginate from fibrinolyticimpairment and hyper-coagulability of HIV-1 infected patients receivingsuch therapy.

[0039] The compounds of the invention may be used for the treatment ofdiabetic nephropathy and renal dialysis associated with nephropathy.

[0040] The compounds of the invention may be used to treat cancer,septicemia, obesity, insulin resistance, proliferative diseases such aspsoriasis, improving coagulation homeostasis, cerebrovascular diseases,microvascular disease, hypertension, dementia, osteoporosis, arthritis,asthma, heart failure, arrhythmia, angina, and as a hormone replacementagent, treating, preventing or reversing progression of atherosclerosis,Alzheimer's disease, osteoporosis, osteopenia; reducing inflammatorymarkers, reducing C-reactive protein, or preventing or treating lowgrade vascular inflammation, stroke, dementia, coronary heart disease,primary and secondary prevention of myocardial infarction, stable andunstable angina, primary prevention of coronary events, secondaryprevention of cardiovascular events, peripheral vascular disease,peripheral arterial disease, acute vascular syndromes, reducing the riskof undergoing a myocardial revascularization procedure, microvasculardiseases such as nephropathy, neuropathy, retinopathy and nephroticsyndrome, hypertension, Type I and 2 diabetes and related diseases,hyperglycemia, hyperinsulinemia, malignant lesions, premalignantlesions, gastrointestinal malignancies, liposarcomas and epithelialtumors, proliferative diseases such as psoriasis, improving coagulationhomeostasis, and/or improving endothelial function, and all forms ofcerebrovascular diseases.

[0041] The compounds of the invention may be used for the topicalapplications in wound healing for prevention of scarring.

[0042] The compounds in the invention can be used in the treatment ofinflammatory diseases, septic shock and the vascular damage associatedwith infections and for the treatment of blood and blood products usedin dialysis, blood storage in the fluid phase, especially ex vivoplatelet aggregation. The compounds in the present invention may also beused in combination with prothrombolytic, fibrinolytic and anticoagulantagents. The present compounds may also be added to human plasma duringthe analysis of blood chemistry in hospital settings to determine thefibrinolytic capacity thereof.

[0043] This invention further comprises methods for treating,preventing, ameliorating or inhibiting each of the maladies mentionedherein in a mammal, preferably in a human, the method(s) each comprisingadministering to a mammal in need of such treatment, prevention,amelioration or inhibition a pharmaceutically or therapeuticallyeffective amount of a compound of this invention, or a pharmaceuticallyacceptable salt or ester form thereof.

[0044] The compounds of the present invention may also be used to treatcancer including, but not limited to, breast and ovarian cancer, and asimaging agents for the identification of metastatic cancers.

[0045] It will be understood that a pharmaceutically or therapeuticallyeffective amount of a compound herein refers to an amount of thecompound in question which will sufficiently inhibit the serine proteaseinhibitor PAI-1 in the mammal in need thereof to a sufficient extent toprovide a desirable improvement in the condition in question or providesufficient inhibition of the serine protease inhibitor PAI-1 to prevent,inhibit or limit the onset of the physiological basis for the malady orcondition in question.

[0046] A subset of the compounds of this invention are those of theFormula I:

[0047] wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, A, n, and R₈ are as definedabove, or a pharmaceutically acceptable salt thereof.

[0048] A further subset of the preferred compounds of this inventioncomprises those having the Formula I:

[0049] wherein:

[0050] R₁, R₂, and R₃, are each, independently, hydrogen, alkyl of 1-3carbons, cycloalkyl of 3-5 carbons, alkanoyl of 1-3 carbons, halogen,hydroxy, aryl optionally substituted with from 1 to 3 groups selectedfrom R₆, perfluoroalkyl of 1-3 carbons, alkoxy of 1-3 carbons, amino,alkylamino of 1-3 carbons, dialkylamino of 1-3 carbons per alkyl group,perfluoroalkoxy of 1-3 carbons;

[0051] R₄ is hydrogen, alkyl of 1-6 carbons, perfluoroalkyl of 1-6carbons, aryl substituted with R₆,

[0052] alkanoyl of 1-6 carbons, aroyl optionally substituted with from 1to 3 groups selected from R₆;

[0053] R₅ is hydrogen, alkyl of 1-6 carbons, alkylaryl, benzyloptionally substituted with from 1 to 3 groups selected from R₆,alkanoyl of 1-6 carbons, aroyl substituted with R₆;

[0054] A is COOH or tetraazole;

[0055] R₆ is hydrogen, alkyl of 1-3 carbons, cycloalkyl of 3-5 carbons,—CH₂-cycloalkyl of 3-5 carbons, alkanoyl of 1-3 carbons, halogen,hydroxy, perfluoroalkyl of 1-3 carbons, alkoxy of 1-3 carbons, amino,alkylamino of 1-3 carbons, dialkylamino of 1-3 carbons, perfluoroalkoxyof 1-3 carbons;

[0056] or a pharmaceutically acceptable salt or ester form thereof.

[0057] Among the specifically preferred compounds of this invention are:

[0058]1-Benzyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indoleor a pharmaceutically acceptable salt thereof;

[0059] 6-(1-Benzyl-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl1H-tetraazol-5-ylmethyl ether or1-Benzyl-2-[5-bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1H-indolor a pharmaceutically acceptable salt thereof;

[0060]1-Methyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indoleor a pharmaceutically acceptable salt thereof;

[0061]2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-methyl-3-pentyl-1H-indoleor 1-Bromo-6-(1-methyl-3-pentyl-1H-indol-2-yl)-2-naphthyl1H-tetraazol-5-ylmethyl ether or a pharmaceutically acceptable saltthereof;

[0062]1-Acetyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indoleor a pharmaceutically acceptable salt thereof;

[0063]1-Acetyl-2-[5-bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1H-indoleor pharmaceutically acceptable salt thereof;

[0064]3-Pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-[2-(trifluoromethyl)benzyl]-1H-indoleor a pharmaceutically acceptable salt thereof;

[0065]2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1-[2-(trifluoromethyl)benzyl]1H-indoleor a pharmaceutically acceptable salt thereof;

[0066]1-(4-tert-Butylbenzyl)-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indoleor a pharmaceutically acceptable salt thereof;

[0067]2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-(4-tert-butylbenzyl)-3-pentyl-1H-indoleor a pharmaceutically acceptable salt thereof;

[0068]{[1-Bromo-6-(1-methyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acidor a pharmaceutically acceptable salt thereof.

[0069] This invention describes the composition and utility ofSubstituted Naphthyl Indole Derivatives of Formula I,

[0070] Wherein:

[0071] R₁, R₂, R₃, R₄ are independently one or more groups selected fromhydrogen, alkyl, cycloalkyl, alkanoyl, halogen, hydroxy, aryl,substituted aryl, perfluoroalkyl, alkoxy, amino, alkylamino,dialkylamino, perfluoroalkoxy,

[0072] R₅ is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl, aryl,substituted aryl, alkanoyl, aroyl,

[0073] R₆ is a group selected from hydrogen, alkyl, alkylaryl, benzyl,substituted benzyl, alkanoyl, aroyl,

[0074] R₇ is a group selected from hydrogen, alkyl, alkylaryl, aryl,substituted aryl,

[0075] n is an integer of 0-6,

[0076] A is COOH, or an acid mimic such as tetraazole, SO₃H, PO₃H₂,tetronic acid, etc.

[0077] Process of the Invention

[0078] The compounds of the present invention can be readily preparedaccording to the following reaction schemes or modification thereofusing readily available starting materials, reagents and conventionalsynthetic procedures. It is also possible to make use of variants ofthese process steps, which in themselves are known to and well withinthe preparatory skill of the medicinal chemist. In the followingreaction schemes, R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are selected from thegroups defined above.

[0079] In Scheme I, methoxy-naphthaldehydes (1) are converted to ketones2 in a two step process. The first part utilizes Grignard chemistry toobtain an intermediate alcohol which is converted to the ketone viaoxidation incorporating PCC or MnO₂. Compounds 2 were then subjected toFisher type indole syntheses to generate the naphthyl indole corestructures (3) using either an aryl hydrazine or an N-arylhydrazone. Inthe case where the hydrazone was used, varied substitution can beintroduced into the indole framework; hydrazones can be generated usinga recent procedure from JACS, S. Wagaw; B. H. Yang; S. L. Buchwald.JACS, 121, 1999, 10251-10263. At this point, the synthetic strategy cantake one of two pathways, A and/or B. In Path A, naphthyl indoles 3 areN-alkylated (R₆X equals alkyl halide such as methyl iodide) orN-acylated ((R₆)₂O equals anhydride such as acetic anhydride) to affordintermediates such as compounds 4. These compounds are demethylatedusing boron tribromide to produce naphthols 5. Compounds 5 areO-alkylated using a variety of alkyl halides and cesium carbonate inacetone to generate the precursor compounds 8 to the target acids (9).The Z group on compounds 8 is a acid precursor such as a carboxylicester or nitrile which can be converted to the carboxylic acids ortetraazoles (9) via hydrolysis or tetraazole formation respectively. Analternative route to acids 9 incorporating Path B also starts withnaphthyl indoles 3. These indoles are first demethylated with borontribromide to produce naphthols 6. Compounds 6 are O-alkylated using avariety of alkyl halides and cesium carbonate in acetone to generateindoles 7. These compounds are N-alkylated or N-acylated as in Path A toonce again afford precursor compounds 8. At this point, Z groups areconverted to the acids of compounds 9 as prevsiously described.

[0080] This invention also provides pharmaceutical compositionscomprised of substituted naphthyl indole derivatives (I) either alone orin combination with excipients (i.e. pharmaceutically acceptablematerials with no pharmacological effects). Such compositions fortreating conditions resulting from fibrinolytic disorder such as deepvein thrombosis and coronary heart disease, pulmonary fibrosis, etc.

[0081] The precise dosage to be employed depends upon several factorsincluding the host, whether in veterinary medicine or human medicine,the nature and severity of the condition being treated, the mode ofadministration and the particular active substance employed. Thecompounds may be administered by any conventional route, in particularenterally, preferably orally in the form of tablets or capsules.Administered compounds can be in the free form or pharmaceuticallyacceptable salt form as appropriate, for use as a pharmaceutical,particularly for use in the prophylactic or curative treatment ofatherosclerosis and sequelae (angina pectoris, myocardial infarction,arrhythmias, heart failure, kidney failure, stroke, peripheral arterialocclusion, and related disease states). These measures will slow therate of progress of the disease state and assist the body in reversingthe process direction in a natural manner.

[0082] Any suitable carrier known to the art can be used to prepare thepharmaceutical compositions. In such a composition, the carrier may be asolid, liquid or mixture of a solid and a liquid. Solid compositionsinclude powders, tablets and capsules. A solid carrier can be one ormore substances which may also act as a flavoring agent, lubricant,solubilizer, suspending agent, binder, or tablet disintegrant. Inpowders, the carrier is a finely divided solid, which is in admixturewith the finely divided active ingredient. In tablets, the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. Suitable solid carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methyl cellulose, hydroxymethyl cellulose, sodiumcarboxymethyl cellulose, a low melting wax, cocoa butter, and the like.Encapsulating materials may also be employed with the compounds of thisinvention, and the term “composition” is intended to include the activeingredient in combination with an encapsulating material as aformulation, with or without other carriers. Cachets may also be used inthe delivery of the anti-atherosclerotic medicament of this invention.

[0083] Sterile liquid compositions include solutions, suspensions,emulsions, syrups and elixirs. The compounds of this invention may bedissolved or suspended in the pharmaceutically acceptable carrier, suchas sterile water, sterile organic solvent or a mixture of both.Preferably the liquid carrier is one suitable for parental injection.Where the compounds are sufficiently soluble they can be dissolveddirectly in normal saline with or without the use of suitable organicsolvents, such as propylene glycol or polyethylene glycol. If desired,dispersions of the finely divided compounds can be made-up in aqueousstarch or sodium carboxymethyl cellulose solution, or in a suitable oil,such as arachis oil. Liquid pharmaceutical compositions, which aresterile solutions or suspensions, can be utilized by intramuscular,intraperitoneal or subcutaneous injection. In many instances a liquidcomposition form may be used instead of the preferred solid oral methodof administration.

[0084] It is preferred to prepare unit dosage forms of the compounds forstandard administration regimens. In this way, the composition can besubdivided readily into smaller doses at the physicians direction. Forexample, unit dosages may be made up in packeted powders, vials orampoules and preferably in capsule or tablet form. The active compoundpresent in these unit dosage forms of the composition may be present inan amount of from about one gram to about fifteen grams or more, forsingle or multiple daily administration, according to the particularneed of the patient. The daily dose of active compound will varydepending upon the route of administration, the size, age and sex of thepatient, the severity of the disease state, and the response to thetherapy as traced by blood analysis and the patients recovery rate. Byinitiating the treatment regimen with a minimal daily dose of about onegram, the blood levels of PAI-1 and the patients symptomatic reliefanalysis may be used to determine whether a larger dose is indicated.Based upon the data presented below, the projected daily dose for bothhuman and veterinary use will be from about 25 to about 200milligrams/kilogram per day, and more usually, from about 50 to about100 milligrams/kilogram per day.

[0085] The ability of the compounds of this invention to inhibitplasminogen activator inhibitor-1 was established by the followingexperimental procedures:

[0086] Primary Screen for the PAI-1 Inhibition

[0087] Test compounds are dissolved in DMSO at a final concentration of10 mM, then diluted 100× in physiologic buffer. The inhibitory assay isinitiated by the addition of test compound (1-100 μM finalconcentration, maximum DMSO concentration of 0.2%) in a pH 6.6 buffercontaining 140 nM recombinant human plasminogen activator inhibitor-1(PAI-1; Molecular Innovations, Royal Oak, Mich.). Following a 1 hourincubation at room temperature, 70 nM of recombinant human tissueplasminogen activator (tPA) is added, and the combination of testcompound, PAI-1 and tPA is incubated for an additional 30 minutes.Following the second incubation, Spectrozyme-tPA (American Diagnostica,Greenwich, Conn.), a chromogenic substrate for tPA, is added andabsorbance read at 405 nm at 0 and 60 minutes. Relative PAI-1 inhibitionis equal to the residual tPA activity in the presence of test compoundand PAI-1. Control treatments include the complete inhibition of tPA byPAI-1 at the molar ratio employed (2:1), and the absence of any effectof the test compound on tPA alone.

[0088] Assay for Determining IC₅₀ of Inhibition of PAI-1

[0089] This assay is based upon the non-SDS dissociable interactionbetween tPA and active PAI-1. Assay plates are initially coated withhuman tPA (10 μg/ml). Test compounds are dissolved in DMSO at 10 mM,then diluted with physiologic buffer (pH 7.5) to a final concentrationof 1-50 μM. Test compounds are incubated with human PAI-1 (50 ng/ml) for15 minutes at room temperature. The tPA-coated plate is washed with asolution of 0.05% Tween 20 and 0.1% BSA, then the plate is blocked witha solution of 3% BSA. An aliquot of the test compound/PAI-1 solution isthen added to the tPA-coated plate, incubated at room temperature for 1hour, and washed. Active PAI-1 bound to the plate is assessed by addingan aliquot of a 1:1000 dilution of the 33B8 monoclonal antibody againsthuman PAI-1, and incubating the plate at room temperature for 1 hour(Molecular Innovations, Royal Oak, Mich.). The plate is again washed,and a solution of goat anti-mouse IgG-alkaline phosphatase conjugate isadded at a 1:50,000 dilution in goat serum. The plate is incubated 30minutes at room temperature, washed, and a solution of alkalinephosphatase substrate is added. The plate is incubated 45 minutes atroom temperature, and color development is determined at OD_(405 nm).The quantitation of active PAI-1 bound to tPA at varying concentrationsof test compound is used to determine the IC₅₀. Results are analyzedusing a logarithmic best-fit equation. The assay sensitivity is 5 ng/mlof human PAI-1 as determined from a standard curve ranging from 0-100ng/ml.

[0090] The compounds of the present invention inhibited PlasminogenActivator Inhibitor-1 as summarized in Table I: TABLE I Compound ofExample IC₅₀ (μM) % Inhibition @ 25 μM 1 9.85^(a) 2 8.8^(b) 3 16.2^(a) 417.4^(b) 5 9.2^(b) 6 — 16^(a) 7 5.22^(a) 8 — 57^(a) 9 24.88^(a) 10 —60^(a) 11 10.73^(a)

[0091]

EXPERIMENTAL EXAMPLES

[0092] The following provides the preparation of representativecompounds of this invention.

Example 11-Benzyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indole

[0093] Step 1

1-(6-Methoxy-2-naphthyl)heptan-1-ol

[0094] To a 3-neck flask equipped with an overhead stirrer, droppingfunnel and thermometer was added 6-methoxy-2-naphthaldehyde (70.760 g,380 mmol) and Et₂O (1400 mL). The stirred suspension under N₂ was cooledin an ice bath followed by the slow addition of hexylmagnesium bromide(228 mL of a 2 M solution in Et₂O) over 1 h. Temperature was kept below12° C. After the addition, the reaction was stirred for 3 h at roomtemperature then cooled in an ice bath and slowly quenched w/saturatedaq. NH₄Cl (250 mL). After quenching, the ice bath was removed and themixture was stirred for a half-hour then diluted with H₂O (750 mL) todissolve all solids. The layers were separated and the aqueous layerextracted with Et₂O (3×200 mL). The combined organics were washed withwater (3×200 mL), and brine (2×200 mL), dried over Na₂SO₄, filtered,rotovap'd and dried in vacuo to give the desired product as an off-whitesolid (101.1 g, 371.2 mmol, 98%) with mp 71-74° C. 15 g of crude alcoholwas recrystallized from hexane to give the desired product as a whitesolid (11.7 g) with mp 71-73° C; ¹H NMR (DMSO-d₆) δ 0.82 (t, J=6.7 Hz,3H), 1.15-1.38 (m, 8H), 1.58-1.71 (m, 2H) 3.85 (s, 3H), 4.58-4.64 (m,1H), 5.14 (d, J=4.3 Hz, 1H), 7.12 (dd, J=2.6, 9.0 Hz, 1H), 7.26 (d, 2.4Hz, 1H), 7.42 (dd, J=1.5, 8.4 Hz, 1H), 7.70 (s, 1H), 7.74 (d, J=8.6 Hz,1H), 7.77 (d, J=8.9 Hz, 1H), IR (solid) 3280, 2920, 2860, 1610, 1270,1170, 1040, and 860 cm⁻¹; mass spectrum [ESI], m/z 255 (MH—H₂O)⁺;

[0095] Anal. Calcd. for C₁₈H₂₄O₂: C, 79.37; H, 8.88; N, 0.00, Found: C,79.27; H, 8.94; N, −0.03.

[0096] Step 2

1-(6-Methoxy-2-naphthyl)heptan-1-one

[0097] To a stirred solution of the 1-(6-methoxy-2-naphthyl)heptan-1-ol(101.1 g, 371 mmol) in CH₂Cl₂ (1000 mL) under N₂ was added pyridiniumchlorochromate (120.02 g, 556.74 mmol). The reaction was stirred for atotal of 3 h and then poured onto an alumina column (2000 g, basicBrockman activity, 60-325 mesh). Column was eluted with CH₂Cl₂. Productwas collected, filtered, rotovap'd and dried in vacuo to give theproduct as a white solid (81.5 g, 301.44 mmol, 81%) with mp 69-72° C.177 mg of crude ketone was recrystallized from methanol to give thedesired product as a white solid (105 mg) mp 70-72° C.; ¹H NMR (DMSO-d₆)δ 0.86 (m, 3H), 1.25-1.40 (m, 6H), 1.60-1.70 (m, 2H), 3.07 (t, J=7.3 Hz,2H), 3.90 (s, 3H), 7.24 (d, J=9 Hz, 1H), 7.39 (s, 1H), 7.87 (d, J=8.7Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 8.02 (d, J =8.9, 1H) 8.58 (s, 1H); IR(solid) 2910, 2870, 1660, 1630, 1470, and 1180 cm⁻¹; mass spectrum [EI],m/z 271 (M+H)⁺;

[0098] Anal. Calcd. for C₁₈H₂₂O₂: C, 79.96; H, 8.20; N, 0.00, Found: C,80.27; H, 8.16; N, 0.02.

[0099] Step 3

2-(6-Methoxy-2-naphthyl)-3-pentyl-1H-indole

[0100] To a stirred suspension of the1-(6-methoxy-2-naphthyl)heptan-1-one (81.5 g, 301.44 mmol) in ethanol(2000 mL) under N₂ was added phenylhydrazine (35.857 g, 331.58 mmol) andp-toluene sulfonic acid monhydrate (120.41 g, 633.02 mmol). The mixturewas refluxed. Warming gave a homogenous solution. (A modification ofthis Fisher indole reaction to incorporate varied substitution on theindole ring utilizes an N-arylhydrazone in place of the arylhydrazine-details of hydrazone preparation in a recent JACS, S.Wagaw; B.H. Yang; S. L. Buchwald. JACS, 121, 1999, 10251-10263). After 92 hreflux, heating was stopped and the reaction mixture cooled androtovap'd to a residue. The residue was partitioned between EtOAc (1700mL) and 1 N HCl (500 mL). The layers were shaken, separated, and theorganic layer washed with 1 N HCl (2×300 mL), sat. aq. NaHCO₃ (3×250mL), H₂O (3×250 mL), brine (2×250 mL), dried over Na₂SO₄, filtered,rotovap'd and dried in vacuo to give a dark viscous oil (106.2 g). Theresidue was triturated with hexane to give an off-white solid which wascollected, rinsed and dried in vacuo to give the product as an off-whitesolid (95.9 g, 279.21 mmol, 93%) which dec. 93-96° C. 400 mg of thecrude indole was recrystallized from hexane to give the product as awhite solid (298 mg) with mp 95-97° C.; ¹H NMR (DMSO-d₆) δ 0.82 (t,J=7.0 Hz, 3H), 1.31 (m, 4H), 1.66 (m, 2H), 2.89 (t, J=7.6 Hz, 2H), 3.90(s, 3H), 6.98-7.02 (m, 1H), 7.07-7.10 (m, 1H), 7.21 (dd, J=2.4, 8.9 Hz,1H), 7.34-7.37 (m, 2H), 7.54 (d, J=7.94 Hz, 1H), 7.73 (dd, J=1.5, 8.6Hz, 1H), 7.88 (d, J=9.00 Hz, 1H), 7.93 (d, J=8.55 Hz, 1H), 8.03 (s, 1H),11.17 (s, 1H); IR (solid) 3350, 2960, 2920, 2840, 1600, 1200, 740, cm⁻¹;mass spectrum [ESI], m/z 344 (M+H)⁺;

[0101] Anal. Calcd. for C₂₄H₂₅NO: C, 83.93; H, 7.34; N, 4.08, Found: C,83.59; H, 7.51; N, 3.86.

[0102] Step 4

1-Benzyl-2-(6-methoxy-2-naphthyl)-3-pentyl-1H-indole

[0103] To a stirred solution of the2-(6-methoxy-2-naphthyl)-3-pentyl-1H-indole (95.5 g, 278.04 mmol) in dryDMF (1000 mL) under N₂ at 0° C. (ice bath) was added k-t-butoxide(32.762 g, 291.95 mmol), portion-wise, over 20 minutes. After theaddition of butoxide, the reaction mixture was stirred for 20 minutesfollowed by the addition of benzylbromide (50.110 g, 291.95 mmol) in oneportion. An exotherm was noted and a precipitate formed. The bath wasremoved 10 minutes later. The reaction was stirred for ˜5 h and thenquenched w/ conc. HOAc (0.05 eq, 13.902 mmol, 0.8 mL) and stirredovernight. The reaction mixture was rotovap'd to a residue which waspartitioned between EtOAc (2 L) and 0.1 N HCl (600 mL). The layers wereseparated and the organic layer was washed with 0.1 N HCl (2×250 mL),H₂O (1×250 mL) and brine (2×250 mL), dried over Na₂SO₄, filtered,rotovap'd and dried to give a brown viscous residue (123.5 g). Thisresidue was dissolved in hexane and flashed on silica (2000 g). Thecolumn was eluted with 1% EtOAc/hexane. The product was collected,filtered, rotovap'd and dried in vacuo to give the product as a viscousyellow oil (109.3 g, 252 mmol, 91%). 300 mg of the yellow oil wasfurther purified by preparatory plate chromatography. The plates wereeluted with 15% ethyl acetate/hexane. The product was collected,filtered, rotovap'd and dried in vacuo at room temperature to give thedesired product as a waxy white solid, mp 76-80° C.; ¹H NMR (DMSO-d₆) δ0.72 (t, J=6.9 Hz, 3H), 1.10-1.20 (m, 4H), 1.51-1.60 (m, 2H), 2.67 (t,J=7.5 Hz, 2H), 3.89 (s, 3H), 5.30 (s, 2H), 6.81 (d, J=7.0 Hz, 2H),7.04-7.22 (m, 6H), 7.34 (d, J=7.9 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.41(dd, J=1.4, 8.4 Hz, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.80-7.84 (m, 2H), 7.87(d, J=8.4 Hz, 1H); IR (solid) 2910, 1605, 1460, 1200, and 740 cm⁻¹; massspectrum [ESI], m/z 434 (M+H)⁺;

[0104] Anal. Calcd. for C₃₁H₃₁NO: C, 85.87; H, 7.21; N, 3.23, Found: C,85.43; H, 7.31; N, 3.14.

[0105] Step 5

6-(1-Benzyl-3-pentyl-1H-indol-2-yl)-2-naphthol

[0106] To a stirred solution of the1-benzyl-2-(6-methoxy-2-naphthyl)-3-pentyl-1H-indole (109.0 g, 251 mmol)in CH₂Cl₂ (1000 mL) under N₂ at −78° C. was added BBr₃ (1M in CH₂Cl₂,302 mL), dropwise, over 1.5 h. After the addition, the reaction waswarmed to 0° C. and stirred for 2.5 h then warmed to rt. After a totalof 5 h the reaction mixture was cooled to 0° C. and quenched with water(250 mL). The mixture was stirred overnight then rotovap'd to a residue.The residue was partitioned between EtOAc (1500 mL) and H₂O (500 mL).The layers were shaken, separated, and the organic layer was washed withH₂O (2×250 mL), brine (2×250 mL), dried over Na₂SO₄, filtered, rotovap'dand dried in vacuo to give a viscous black goo (114 g). The residue wasdissolved in CHCl₃ and flashed on silica (2000 g). The column was elutedwith hexane and 8% EtOAc/Hexane. The product was collected, filtered,rotovap'd and the residue triturated with hexane then dried to give theproduct as an off-white solid (89.2 g, 213 mmol, 85%) with mp 96-100° C.400mg of the crude solid was recrystallized from hexane to give desiredproduct as an off-white solid (311 mg) with mp 97-100° C.; ¹H NMR(DMSO-d₆) δ 0.73 (t, J=6.7 Hz, 3H), 1.10-1.20 (m, 4H), 1.51-1.60 (m,2H), 2.67 (t, J=7.3 Hz, 3H), 5.29 (s, 2H), 6.82 (d, J=7.2 Hz, 2H),7.04-7.20 (m, 7H), 7.30-7.35 (m, 2H), 7.59 (d, J=7.8Hz, 1H), 7.73-7.78(m, 3H); IR (solid) 3380, 2920, 1610, 1200, 740 cm⁻¹; mass spectrum[ES], m/z 420 (M+H)⁺;

[0107] Anal. Calcd. for C₃₀H₂₉NO: C, 85.88; H, 6.97; N, 3.34, Found: C,85.85; H, 7.10; N, 3.20.

[0108] Step 6

{[6-(1-Benzyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile

[0109] To a solution of 6-(1-benzyl-3-pentyl-1H-indol-2-yl)-2-naphthol(19.245 g, 45.868 mmol) in acetone (200 mL) at rt under N₂ was addedCs₂CO₃ (16.439 g, 50.455 mmol) followed by the bromide (6.052 g, 50.455mmol). After stirring for 4.5 h, the reaction was rotovap'd to aresidue. The residue was partitioned between EtOAc (350 mL) and H₂O (150mL). The layers were shaken, separated, and the organic layer washedwith H₂O (2×80 mL), brine (2×80 mL), dried over Na₂SO₄, filtered,rotovap'd, and dried to give a viscous brown oil (20.664 g). The residuewas taken in CHCl₃ and flashed on silica (435 g). The column was elutedwith hexane and 8% EtOAc/Hex. The product was collected, filtered,rotovap'd, triturated with hexane and dried to give the product as awhite solid (18.78 g, 40.95 mmol, 89%) with mp 111-113° C. 400 mg of thecrude product was recrystallized from MeOH to give the desired productas a white solid (0.362 g) with mp 109-112° C.; ¹H NMR (DMSO-d₆) δ 0.72(t, J=6.9 Hz, 3H), 1.10-1.20 (m, 4H), 1.52-1.59 (m, 2H), 2.68 (t, J=7.5Hz, 2H), 5.31 (s, 4H), 6.81 (d, J=7.2 Hz, 2H), 7.05-7.19 (m, 5H), 7.31(dd, J=2.6, 9.0 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.47 (dd, J=1.4, 8.2Hz, 1H) 7.56 (d, J=2.4 Hz, 1H), 7.6 (d, J=7.6 Hz,1H) 7.88-7.94 (m, 3H);IR (solid) 2940, 1610, 1460, and 1200 cm⁻¹; mass spectrum [ESI], m/z 459(M+H)⁺;

[0110] Anal. Calcd. for C₃₂H₃₀N₂O: C, 83.81; H, 6.59; N, 6.11, Found: C,83.93; H, 6.60; N, 6.05.

[0111] Step 7

1-Benzyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indole

[0112] To a stirred solution of the{[6-(1-benzyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (87.0g, 189.71 mmol) in DMF (900 mL) under N₂ was added NaN₃ (61.665 g,948.54 mmol) and NH₄Cl (50.737 g, 948.54 mmol). The reaction was heatedbetween 95-100° C. for 1.33 h then cooled. The reaction mixture wasrotovap'd to a residue and the residue partitioned between EtOAc (2000mL) and 1 N HCl (600 mL). The layers were shaken, separated, and theorganic layer washed with 1 N HCl (2×300 mL), H₂O (3×300 mL), and brine(2×300 mL), dried over Na₂SO₄, filtered, rotovap'd and triturated withhexane to give an off-white solid (97.5 g). The product was purified byrefluxing the solid in diethyl ether (2000 mL), concentrating to about aliter and cooling. The solids were collected and dried in vacuo to givethe product as a white solid (77.4 g, 154.3 mmol, 81%) with dec.111-114° C.; ¹H NMR (DMSO-d₆) δ 0.72 (t, J=6.9 Hz, 3H) 1.10-1.20 (m,4H), 1.50-1.60 (m, 2H), 2.67 (t, J=7.8 Hz, 2H), 5.30 (s, 2H), 5.62 (s,2H), 6.81 (d, J=7.3 Hz, 2H), 7.02-7.20 (m, 5H), 7.30 (dd, J=2.4, 9.0 Hz,1H), 7.35 (d, J=7.9 Hz, 1H), 7.44 (dd, J=1.5, 8.2 Hz, 1H), 7.55 (d,J=2.3 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.84-7.90 (m, 3H) 16.9 (s, 1H);IR (solid) 2920, 2850, 1610, 1390, 1200, 860, and 750, cm¹; massspectrum [ESI], m/z 502 (M+H)⁺;

[0113] Anal. Calcd. for C₃₂H₃₁N₅O: C, 76.62; H, 6.23; N, 13.96, Found:C, 76.43; H, 6.12; N, 14.19.

Example 2 6-(1-Benzyl-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl1H-tetraazol-5-ylmethyl ether or1-Benzyl-2-[5-bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1H-indole

[0114] Step 1

2-(6-Hydroxy-2-naphthyl)-3-pentyl-1H-indole

[0115] To a stirred solution of2-(6-methoxy-2-naphthyl)-3-pentyl-1H-indole (0.915 g, 2.66 mmol) inCH₂Cl₂ (30 mL) cooled to −78° C. was added BBr₃ (9.86 mL, 1.0 M inCH₂Cl₂, 9.86 mmol) dropwise. The reaction was stirred at thistemperature for 0.5 h and then warmed to rt for 2 h. The reactionmixture was quenched with MeOH (˜5 mL) followed by dilution with H₂O (20mL) and EtOAc (200 mL). The organic layer was washed with brine (20 mL)and then dried (Na₂SO₄). After concentration, the residue was purifiedby the Biotage Flash 40 apparatus (10 to 20% EtOAc:petroleum ethergradient) to afford the product (0.677 g, 77%) as a foamy solid; ¹H NMR(DMSO-d₆) δ 0.83 (t, J=7.3 Hz, 3H), 1.23-1.42 (m, 4H), 1.58-1.76 (m,2H), 2.89 (t, J=8.2 Hz, 2H), 7.00 (t, J=8.2 Hz, 1H), 7.06-7.19 (m, 3H),7.35 (d, J=8.2 Hz, 1H), 7.53 (d, J=8.2, 1H), 7.67 (d, J=9.1 Hz, 1H),7.74-7.88 (m, 2H), 7.98 (s, 1H), 9.83 (s, 1H), 11.14 (s, 1H); massspectrum [(+) ESI], m/z 330 (M+H)⁺ and [(−) ESI], m/z 328 (M−H)⁻.

[0116] Step 2

2-(5-Bromo-6-hydroxy-2-naphthyl)-3-pentyl-1H-indole

[0117] To a stirred solution of2-(6-hydroxy-2-naphthyl)-3-pentyl-1H-indole (1.27 g, 3.85 mmol) in HOAc(25 mL) at 0° C. was added KOAc (0.453 g, 4.62 mmol). The reaction wasstirred at this temperature for 10 min., and then a solution of Br₂(0.218 mL, 4.24 mmol) in HOAc (5 mL) was added dropwise to it over aperiod of 10 min. The reaction mixture was allowed to warm to rt andstirred for 4 h. The reaction mixture was then diluted with H₂O (50 mL)and extracted with EtOAc (200 mL). The organic layer was washed withbrine (20 mL) and then dried (Na₂SO₄). After concentration, the residuewas purified by the Biotage Flash 40 apparatus (10 to 30%EtOAc:petroleum ether gradient) to afford the product (0.782 g, 50%) asa solid (inseparable mixture of mono- and di-bromo-substituted analogswhich were separated in the next step); monobrominated compound: massspectrum [(−) ESI], m/z 406/408 (M−H)⁻ and dibrominated analog: massspectrum [(−) ESI], m/z 486 (M−H)⁻.

[0118] Step 3

{[1-Bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile and{[1-Bromo-6-(5-bromo-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile

[0119] To a stirred solution of2-(5-bromo-6-hydroxy-2-naphthyl)-3-pentyl-1H-indole (0.740 g, 1.81 mmol)in acetone (20 mL) at rt was added Cs₂CO₃ (1.30 g, 3.98 mmol) followedby bromoacetonitrile (0.139 mL, 1.99 mmol) dropwise. The reaction wasstirred at this temperature for 6 h and then diluted with EtOAc (200mL). The organic layer was washed with H₂O (20 mL) and brine (20 mL) andthen dried (Na₂SO₄). After concentration, the residue was purified bythe Biotage Flash 40 apparatus (20% EtOAc:petroleum ether) to afford theproduct (0.315 g, 39%) as a foamy solid as well as the dibrominatedanalog (0.141 g, 15%); monobrominated compound. ¹H NMR (DMSO-d₆) δ 0.82(t, J=7.3 Hz, 3H), 1.22-1.42 (m, 4H), 1.60-1.74 (m, 2H), 2.93 (t, J=8.2Hz, 2H), 5.46 (s, 2H), 7.02 (t, J=7.3 Hz, 1H), 7.13 (t, J=7.3 Hz, 1H),7.39 (d, J=8.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.67 (d, J=9.1 Hz, 1H),7.97 (d, J=9.1 Hz, 1H), 8.10-8.28 (m, 3H), 11.31 (s, 1H); mass spectrum[(−) ESI], m/z 445/447 (M−H)⁻ and dibrominated analog: ¹H NMR (DMSO-d₆)δ 0.81 (t, J=7.7 Hz, 3H), 1.21-1.40 (m, 4H), 1.57-1.73 (m, 2H), 2.92 (t,J=8.7 Hz, 2H), 5.46 (s, 2H), 7.16 (d, J=8.7 Hz, 1H), 7.51-7.59 (m, 2H),7.69 (d, J=8.7 Hz, 1H), 7.95 (d, J=9.7 Hz, 1H), 8.12-8.31 (m, 3H), 11.50(s, 1H); mass spectrum [(−) ESI], m/z 525 (M−H)⁻.

[0120] Step 4

{[6-(1-Benzyl-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl]oxy}acetonitrile

[0121] To a stirred solution of{[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (0.135g, 0.257 mmol) in THF (5 mL) at 0° C. was added KOt-Bu (0.032 g, 0.283mmol) followed by BnBr (0.019 mL, 0.308 mmol). The reaction was warmedto rt and let stir for 24 h. After this time, the reaction mixture wasquenched with 1 N HCl (˜2 mL). The resulting solution was diluted withEtOAc (100 mL). The organic layer was washed with 1 N HCl (10 mL), sat.aq. NaHCO₃ (10 mL), and brine (10 mL) and then dried (MgSO₄). Afterconcentration, the residue was purified by preparatory platechromatography (20% EtOAc:petroleum ether) to afford the product (0.105g, 56%) as a solid; ¹H NMR (DMSO-d₆) δ 0.73 (t, J=7.4 Hz, 3H), 1.09-1.23(m, 4H), 1.47-1.63 (m, 2H), 2.70 (t, J=7.7 Hz, 2H), 5.34 (s, 2H), 5.46(s, 2H), 6.81 (d, J=7.4 Hz, 2H), 7.04-7.23 (m, 5H), 7.41 (d, J=8.1 Hz,1H), 7.62-7.73 (m, 3H), 8.02 (s, 1H), 8.12 (d, J=9.2 Hz, 1H), 8.20 (d,J=9.2 Hz, 1H); mass spectrum [(+) ESI], m/z 537/539 (M+H)⁺.

[0122] Step 5

6-(1-Benzyl-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl1H-tetraazol-5-ylmethyl ether or1-Benzyl-2-[5-bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1H-indole

[0123] To a stirred solution of{[6-(1-benzyl-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl]oxy}actonitrile(0.101 g, 0.188 mmol) in DMF (7 mL) at rt was added NaN₃ (0.061 g, 0.940mmol) followed by NH₄Cl (0.050 g, 0.940 mmol). The reaction was heatedto 100° C. for 2 h. After this time, it was concentrated and dilutedwith 2 N HCl (˜5 mL). This mixture was stirred at rt for 2 h and thenextracted with EtOAc (100 mL). The organic layer was washed with 2 N HCl(10 mL) and brine (10 mL) and then dried (MgSO₄). The resulting solutionwas concentrated to afford the product (0.065 g, 60%) as a yellow foam,mp >70° C. (decomp.); ¹H NMR (DMSO-d₆) δ 0.72 (t, J=6.9 Hz, 3H),1.09-1.20 (m, 4H), 1.50-1.59 (m, 2H), 2.68 (t, J=7.3 Hz, 2H), 5.32 (s,2H), 5.71 (s, 2H), 6.77-6.81 (m, 2H), 7.07 (t, J=7.6 Hz, 1H), 7.10-7.18(m, 4H), 7.38 (d, J=8.1 Hz, 1H), 7.58-7.64 (m, 2H), 7.70 (d, J=9.0 Hz,1H), 7.97 (s, 1H), 8.03 (d, J=9.2 Hz, 1H), 8.15 (d, J=8.9 Hz, 1H),15.90-17.70 (bs, 1H); IR (neat) 3030, 2950, 2925, 2855, 1600, 1565,1495, 1475, 1465, 1455, 1405, 1330, 1270, 1745, 1195, 1145, 1050, 1030,1020, 975, 920, 895, 830, 800, 740, 700, and 675 cm⁻¹; mass spectrum[(−) ESI], m/z 578 (M−H)⁻;

[0124] Anal. Calcd. for C₃₂H₃₀BrN₅O.1.5H₂O: C, 63.26; H, 5.47; N, 11.53,Found: C, 63.16; H, 5.11; N, 11.33.

Example 31-Methyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indole

[0125] Step 1

{[6-(3-Pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile

[0126] The title compound was prepared as a solid (0.633 g, 84%) from2-(6-hydroxy-2-naphthyl)-3-pentyl-1H-indole using the procedure fromstep 3 of Example 2; ¹H NMR (DMSO-d₆) δ 0.83 (t, J=7.5 Hz, 3H),1.24-1.42 (m, 4H), 1.60-1.75 (m, 2H), 2.93 (t, J=8.4 Hz, 2H), 5.33 (s,2H), 7.02 (t, J=8.4 Hz, 1H), 7.11 (t, J=8.4 Hz, 1H), 7.28-7.41 (m, 2H),7.52-7.62 (m, 2H), 7.80 (d, J=9.3 Hz, 1H), 7.99 (d, J=9.3 Hz, 2H), 8.13(s, 1H), 11.23 (s, 1H); mass spectrum [(−) ESI], m/z 367 (M−H)⁻.

[0127] Step 2

{[6-(1-Methyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile

[0128] The title compound was prepared as a solid (0.412 g, 83%) from{[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using Mel andthe procedure from step 4 of Example 2; ¹H NMR (DMSO-d₆) δ 0.74 (t,J=7.5 Hz, 3H), 1.07-1.27 (m, 4H), 1.47-1.65 (m, 2H), 2.68 (t, J=8.3 Hz,2H), 3.59 (s, 3H), 5.34 (s, 2H), 7.08 (t, J=8.3 Hz, 1H), 7.19 (t, J=8.3Hz, 1H), 7.34 (dd, J=1.5, 9.0 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.53-7.66(m, 3H), 7.92-8.08 (m, 3H); mass spectrum [(+) ESI], m/z 383 (M+H)⁺.

[0129] Step 3

1-Methyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indole

[0130] The title compound was prepared as a lt. tan solid (0.311 g, 74%)from {[6-(1-methyl-3-pentyl-1H-indole-2-yl)-2-naphthyl]oxy}acetonitrileusing the procedure from step 5 of Example 2, mp 120-122° C.; ¹H NMR(DMSO-d₆) δ 0.73 (t, J=6.9 Hz, 3H), 1.09-1.24 (m, 4H), 1.48-1.60 (m,2H), 2.66 (t, J=7.2 Hz, 2H), 3.58 (s, 3H), 5.65 (s, 2H), 7.06 (t, J=7.6Hz, 1H), 7.18 (t, J=7.4 Hz, 1H), 7.33 (dd, J=2.5, 8.9 Hz, 1H), 7.45 (d,J=8.1 Hz, 1H), 7.51-7.62 (m, 3H), 7.91-8.01 (m, 3H), 15.08-17.10 (bs,1H); IR (neat) 3130, 3040, 2950, 2930, 2890, 2860, 2795, 1625, 1605,1565, 1500, 1485, 1470, 1440, 1430, 1390, 1360, 1340, 1325, 1265, 1230,1220, 1200, 1170, 1135, 1100, 1045, 1035,1015, 965, 930, 905, 845,830,785, 740, 705, and 680 cm⁻¹; mass spectrum [(+) APCl], m/z 426(M+H)⁺;

[0131] Anal. Calcd. for C₂₆H₂₇N₅O: C, 73.39; H, 6.40; N, 16.46, Found:C, 73.08; H, 6.57; N, 16.45.

Example 4 2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-methyl-3-pentyl-1H-indole or1-Bromo-6-(1-methyl-3-pentyl-1H-indol-2-yl)-2-naphthyl1H-tetraazol-5-ylmethyl ether

[0132] Step 1

{[6-(1-Methyl-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl]oxy}acetonitrile

[0133] The title compound was prepared as a solid (0.111 g, 69%) from{[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile usingMel and the procedure from step 4 of Example 2; ¹H NMR (DMSO-d6) δ 0.73(t, J =7.4 Hz, 3H), 1.08-1.26 (m, 4H), 1.47-1.62 (m, 2H), 2.69 (t, J=8.2Hz, 2H), 3.61 (s, 3H), 5.48 (s, 2H), 7.09 (t, J=7.4 Hz, 1H), 7.21 (t,J=7.4 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.68-7.80(m, 2H), 8.08 (s, 1H), 8.22 (d, J=8.9 Hz, 1H), 8.27 (d, J=8.9 Hz, 1H);mass spectrum [(+) ESI], m/z 461/463 (M+H)⁺.

[0134] Step 2

2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-methyl-3-pentyl-1H-indoleor 1-Bromo-6-(1-methyl-3-pentyl-1H-indol-2-yl)-2-naphthyl1H-tetraazol-5-ylmethyl ether

[0135] The title compound was prepared as a lt. brown solid (0.070 g,61%) from {[6-(1-methyl-3-pentyl-1H-indole-2-yl)-1-bromo-2-naphthyl]oxy}acetonitrileusing the procedure from step 5 of Example 2, mp>125° C. (decomp.); ¹HNMR (DMSO-d₆,) δ 0.73 (t, J=6.9 Hz, 3H), 1.11-1.21 (m, 4H), 1.50-1.57(m, 2H), 2.66 (t, J=7.5 Hz, 2H), 3.59 (s, 3H), 5.60 (s, 2H), 7.07 (t,J=7.2 Hz,1H), 7.19 (t, J=7.3 Hz, 1H), 7.46 (d, J=8.2 Hz,1H), 7.58 (d,J=7.9 Hz,1H), 7.68 (d, J=8.7 Hz,1H), 7.81 (d, J=9.0 Hz, 1H), 8.01 (s,1H), 8.09 (d, J=9.0 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 15.95-17.95 (bs,1H); IR (neat) 3050, 2950, 2920, 2855, 1600, 1565, 1475, 1470, 1405,1365, 1330, 1270, 1245, 1185, 1160, 1150, 1135, 1100, 1055, 1020, 975,915, 895, 825, 800, 765, 740, 700, and 670 cm⁻¹; mass spectrum [(−)ESI], m/z 502 (M−H)⁻;

[0136] Anal. Calcd. for C₂₆H₂₆BrN₅O.1.25H₂O: C, 59.26; H, 5.45; N,13.29, Found: C, 58.89; H, 5.07; N, 12.83.

Example 51-Acetyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indole

[0137] Step 1

{[6-(1-Acetyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile

[0138] To a stirred solution of{[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (0.300 g, 0.814mmol) in Ac₂O (3 mL, 3.18 mmol) at rt was added a catalytic amount ofCSA (0.019 g, 0.0814 mmol). The reaction was heated to 70° C. for 18 h,and by TLC the reaction was about one half complete. Another 19 mg ofCSA added and kept at 70° C. for an additional 24 h. After this time,the reaction mixture was quenched with 1 N HCl (˜2 mL). The resultingsolution was extracted with EtOAc (100 mL). The organic layer was washedwith 1 N HCl (10 mL), sat. aq. NaHCO₃ (10 mL), and brine (10 mL) andthen dried (MgSO₄). After concentration, the residue was purified by theBiotage Flash 40 apparatus (10 to 20% EtOAc:petroleum ether gradient) toafford the product (0.164 g, 49%) as a solid; ¹H NMR (DMSO-d₆) δ 0.73(t, J=7.2 Hz, 3H), 1.03-1.23 (m, 4H), 1.47-1.61 (m, 2H), 1.92 (s, 3H),3.24-3.42 (m, 2H), 5.34 (s, 2H), 7.27-7.43 (m, 3H), 7.52-7.70 (m, 3H),7.94-8.08 (m, 3H), 8.33 (d, J=8.8 Hz, 1H); mass spectrum [(+) ESI], m/z411 (M+H)⁺, 433 (M+Na)⁺.

[0139] Step 2

1-Acetyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indole

[0140] The title compound was prepared as a yellow foamy solid (0.097 g,56%) from{[6-(1-acetyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile usingthe procedure from step 5 of Example 2, mp>95° C. (decomp.); ¹H NMR(DMSO-d₆) δ 0.71 (t, J=7.0 Hz, 3H), 1.08-1.19 (m, 4H), 1.47-1.56 (m,2H), 1.90 (s, 3H, 2.51 (t, J=7.6 Hz, 2H), 5.55 (s, 2H), 7.29-7.38 (m,3H), 7.52 (dd, J=1.5, 8.4 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.63 (d,J=7.2 Hz, 1H), 7.92-7.98 (m, 3H), 8.31 (d, J=7.8 Hz, 1H), 14.75-17.75(bs, 1H); IR (neat) 3050, 2955, 2925, 2860, 1695, 1630, 1610, 1575,1500, 1475, 1455, 1370, 1335, 1305, 1265, 1240, 1200, 1170, 1155, 1130,1100, 1060, 1025, 950, 920, 900, 865, 810, 750, 700, and 675 cm⁻¹; massspectrum [(+) ESI], m/z 454 (M+H)⁺;

[0141] Anal. Calcd. for C₂₇H₂₇N₅O₂.2.0H₂O: C, 66.24; H, 6.38; N, 14.30,Found: C, 65.85; H, 5.76; N, 13.53.

Example 61-Acetyl-2-[5-bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1H-indole

[0142] Step 1

{[6-(1-Acetyl-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl]oxy}acetonitrile

[0143] The title compound was prepared as a solid (0.093 g, 31%) from{[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile usingthe procedure from step 1 of Example 5; ¹H NMR (DMSO-d₆) δ 0.72 (t,J=7.2 Hz, 3H), 1.07-1.21 (m, 4H), 1.48-1.59 (m, 2H), 1.97 (s, 3H),2.42-2.57 (m, 2H), 5.48 (s, 2H), 7.27-7.46 (m, 2H), 7.63-7.80 (m, 3H),8.13 (s, 1H), 8.15-8.36 (m, 3H); mass spectrum [(+) ESI], m/z 489/491(M+H)⁺, 511/513 (M+Na)⁺.

[0144] Step 2

1-Acetyl-2-[5-bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1H-indole

[0145] The title compound was prepared as a light yellow foam (0.028 g,29%) from{[6-(1-acetyl-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl]oxy}acetonitrileusing the procedure from step 5 of Example 2, mp>79° C. (decomp.); ¹HNMR (DMSO-d₆) δ 0.71 (t, J=7.0 Hz, 3H), 1.08-1.18 (m, 4H), 1.48-1.56 (m,2H), 1.95 (s, 3H), 2.48-2.56 (m, 2H), 5.73 (s, 2H), 7.32 (td, J=1.1, 7.5Hz, 1H), 7.37 (td, J=1.2, 7.3 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.70 (dd,J=1.7, 8.7 Hz, 1H), 7.74 (d, J=9.0 Hz, 1H), 8.08 (d, J=1.5 Hz, 1H), 8.12(d, J=9.0 Hz, 1H), 8.20 (d, J =8.7 Hz, 1H), 8.30 (d, J=7.8 Hz, 1H),14.75-17.75 (bs, 1H); IR (neat) 3140, 3050, 2950, 2920, 2860, 2630,1695, 1630, 1600, 1570, 1475, 1450, 1370, 1340, 1300, 1270, 1245, 1205,1195, 1140, 1095, 1045, 1020, 980,-915, 900, 875, 830, 805,750, 700, and670 cm⁻¹; mass spectrum [(+) ESI], n/z 532/534 (M+H)⁺;

[0146] Anal. Calcd. for C₂₇H₂₆BrN₅O₂.1.0H₂O: C, 58.92; H, 5.13; N,12.72, Found: C, 58.74; H, 4.76; N, 12.21.

Example 73-Pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-[2-(trifluoromethyl)benzyl]-1H-indole

[0147] Step 1

{[6-(3-Pentyl-1-[2-(trifluoromethyl)benzyl]-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile

[0148] The title compound was prepared as a solid (0.147 g, 34%) from{[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using2-trifluoromethyl benzyl bromide and the procedure from step 4 ofExample 2; ¹H NMR (DMSO-d₆) δ 0.72 (t, J=7.8 Hz, 3H), 1.08-1.29 (m, 4H),1.51-1.67 (m, 2H), 2.71 (t, J=8.6 Hz, 2H), 5.29 (s, 2H), 5.47 (s, 2H),6.37 (d, J=8.6 Hz, 1H), 7.08-7.21 (m, 2H), 7.23-7.32 (m, 2H), 7.35-7.45(m, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.63-7.75 (m,2H), 7.83-7.92 (m, 3H); mass spectrum [(+) ESI], m/z 527 (M+H)⁺.

[0149] Step 2

3-Pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-[2-(trifluoromethyl)benzyl]-1H-indole

[0150] The title compound was prepared as a lt. brown/tan solid (0.097g, 66%) from{[6-(3-pentyl-1-[2-(trifluoromethyl)benzyl]-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrileusing the procedure from step 5 of Example 2, mp>100° C. (decomp.); ¹HNMR (DMSO-d₆) δ 0.73 (t, J=7.0 Hz, 3H), 1.11-1.27 (m, 4H), 1.53-1.63 (m,2H), 2.70 (t, J=7.5 Hz, 2H), 5.46 (s, 2H), 5.60 (s, 2H), 6.36 (d, J=7.8Hz, 1H), 7.09-7.17 (m, 2H), 7.24 (d, J=7.5 Hz, 1H), 7.28 (dd, J=2.4, 9.0Hz, 1H), 7.34-7.40 (m, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.52 (d, J=2.3 Hz,1H), 7.64 (d, J=7.6 Hz, 1H), 7.67 (d, J=6.9 Hz, 1H), 7.79-7.85 (m, 3H),16.15-17.50 (bs, 1H); IR (neat) 3040, 2950, 2930, 2860, 1630, 1605,1570, 1480, 1460, 1445, 1390, 1340, 1310, 1255, 1230, 1205, 1165, 1120,1060, 1035, 930, 900, 865, 805, 775, 745, 725, and 660 cm⁻¹; massspectrum [(−) ESI], m/z 568(M−H)⁻;

[0151] Anal. Calcd. for C₃₃H₃₀F₃N₅O.0.5H₂O: C, 68.50; H, 5.40; N, 12.10,Found: C, 68.63; H, 5.34; N, 11.87.

Example 82-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1-[2-(trifluoromethyl)benzyl]-1H-indole

[0152] Step 1

{[6-(3-Pentyl-1-[2-(trifluoromethyl)benzyl]-1H-indol-2-yl)-1-bromo-2-naphthyl]oxy}acetonitrile

[0153] The title compound was prepared as a solid (0.053 g, 14%) from{[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using2-trifluoromethyl benzyl bromide and the procedure from step 4 ofExample 2; ¹H NMR (DMSO-d₆) δ 0.72 (t, J=7.0 Hz, 3H), 1.11-1.22 (m, 4H),1.54-1.62 (m, 2H), 2.71 (t, J=7.4 Hz, 2H), 5.42 (s, 2H), 5.48 (s, 2H),6.34 (d, J=7.9 Hz, 1H), 7.11-7.20 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 7.37(t, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.57 (dd, J=1.7, 8.9 Hz, 1H),7.63-7.68 (m, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.95 (d, J=1.2 Hz, 1H), 8.03(d, J=9.2 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H).

[0154] Step 2

2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1-[2-(trifluoromethyl)benzyl]-1H-indole

[0155] The title compound was prepared as a yellow foam (0.013 g, 25%)from{[6-(3-pentyl-1-[2-(trifluoromethyl)benzyl]-1H-indol-2-yl)-1-bromo-2-naphthyl]oxy}-acetonitrileusing the procedure from step 5 of Example 2, mp>85° C. (decomp.); ¹HNMR (DMSO-d₆) δ 0.73 (t, J=6.9 Hz, 3H), 1.10-1.23 (m, 4H), 1.54-1.62 (m,2H), 2.70 (t, J=7.33 Hz, 2H), 5.47 (s, 2H), 5.70 (s, 2H), 6.34 (d, J=7.8Hz, 1H), 7.11-7.18 (m, 2H), 7.27 (d, J=7.6 Hz, 1H), 7.37 (t, J=7.5 Hz,1H), 7.45 (t, J=7.6 Hz, 1H), 7.54 (dd, J=1.5, 8.7 Hz, 1H), 7.63 (d,J=7.6 Hz, 1H), 7.65-7.70 (m, 2H), 7.91 (d, J=1.4 Hz, 1H), 7.97 (d, J=9.0Hz, 1H), 8.08 (d, J=8.7 Hz, 1H), 15.75-17.85 (bs, 1H); IR (neat) 3050,2950, 2920, 2855, 1600, 1565, 1475, 1460, 1415, 1355, 1335, 1310, 1270,1245, 1195, 1160, 1115, 1075, 1060, 1035, 970, 925, 895, 830, 795, 770,740, and 650 cm⁻¹; mass spectrum [(+) ESI], m/z 648 (M+H)⁺ and [(−)ESI], m/z 646 (M−H)⁻;

[0156] Anal. Calcd. for C₃₃H₂₉BrF₃N₅O.3.3H₂O: C, 55.99; H, 5.07; N,9.89, Found: C, 56.14; H, 4.36; N, 9.44.

Example 91-(4-tert-Butylbenzyl)-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indole

[0157] Step 1

{[6-(1-[4-tert-Butylbenzyl]-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile

[0158] The title compound was prepared as a solid (0.191 g, 46%) from{[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using4-tert-butylbenzyl bromide and the procedure from step 4 of Example 2;¹H NMR (DMSO-d₆) δ 0.73 (t, J=7.4 Hz, 3H), 1.08-1.27 (m, 4H), 1.17 (s,9H), 1.48-1.65 (m, 2H), 2.69 (t, J=8.1 Hz, 2H), 5.29 (s, 2H), 5.52 (s,2H), 6.78 (d, J=8.1 Hz, 2H), 7.05-7.14 (m, 2H), 7.18 (d, J=8.1 Hz, 2H),7.32 (dd, J=1.4, 9.9 Hz, 1H), 7.38 (d, J=7.4, 1H), 7.53 (d, J=8.5 Hz,1H), 7.58-7.67 (m, 2H), 7.90-8.00 (m, 3H); mass spectrum [(+) ESI], m/z515 (M+H)⁺, 537 (M+Na)⁺ and [(−) ESI], m/z 513 (M−H)⁻.

[0159] Step 2

1-(4-tert-Butylbenzyl)-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indole

[0160] The title compound was prepared as a yellow foamy solid (0.144 g,73%) from{[6-(1-[4-tert-butylbenzyl]-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrileusing the procedure from step 5 of Example 2, mp>95° C. (decomp.); ¹HNMR (DMSO-d₆) δ 0.73 (t, J=6.7 Hz, 3H), 1.12-1.20 (m, 4H), 1.16 (s, 9H),1.52-1.58 (m, 2H), 2.67 (t, J=7.5 Hz, 2H), 5.26 (s, 2H), 5.60 (t, 2H),6.76 (d, J=8.2 Hz, 2H), 7.05 (t, J=7.5 Hz,1H), 7.10 (t, J=7.8 Hz,1H),7.17 (d, J=8.2 Hz, 2H), 7.30 (dd, J=2.3, 9.0 Hz, 1H), 7.35 (d, J=7.9 Hz,1H), 7.47 (dd, J=1.2, 8.6 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 7.59 (d,J=7.8 Hz, 1H), 7.87-7.92 (m, 3H), 14.75-17.75 (bs, 1H); IR (neat) 3060,2950, 2925, 2850, 1630, 1605, 1565, 1515, 1500, 1480, 1465, 1445, 1410,1395, 1365, 1345, 1305, 1270, 1235, 1200, 1170, 1130, 1105, 1030, 1010,965, 930, 900, 855, 810, 740, and 670 cm⁻¹; mass spectrum [(−) ESI], m/z556 (M−H)⁻;

[0161] Anal. Calcd. for C₃₆H₃₉N₅O.0.75H₂O: C, 75.69; H, 7.15; N, 12.26,Found: C, 75.84; H, 6.92; N, 12.30.

Example 102-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-(4-tert-butylbenzyl)-3-pentyl-1H-indole

[0162] Step 1

{[6-(1-[-4-tert-Butylbenzyl]-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl]oxy}acetonitrile

[0163] The title compound was prepared as a solid (0.070 g, 19%) from{[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using4-tert-butylbenzyl bromide and the procedure from step 4 of Example 2;¹H NMR (DMSO-d₆) δ 0.73 (t, J=7.3 Hz, 3H), 1.06-1.30 (m, 4H), 1.15 (s,9H), 1.48-1.63 (m, 2H), 2.69 (t, J=8.4 Hz, 1H), 5.31 (s, 2H), 5.47 (s,2H), 6.74 (d, J=8.4 Hz, 2H), 7.05-7.17 (m, 3H), 7.17 (d, J=8.4 Hz, 2H),7.42 (d, J=8.7 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.70 (d, J=9.1 Hz, 2H),8.05 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H); massspectrum [(+) ESI], m/z 593/595 (M+H)⁺.

[0164] Step 2

2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-(4-tert-butylbenzyl)-3-pentyl-1H-indole

[0165] The title compound was prepared as a yellow foam (0.042 g, 56%)from{[6-(1-[-4-tert-butylbenzyl]-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl]oxy}acetonitrileusing the procedure from step 5 of Example 2, mp>90° C. (decomp.); ¹HNMR (DMSO-d₆) δ 0.72 (t, J=7.0 Hz, 3H), 1.11-1.18 (m, 4H), 1.15 (s, 9H),1.52-1.58 (m, 2H), 2.68 (t, J=7.3 Hz, 2H), 5.28 (s, 2H), 5.72 (s, 2H),6.74 (d, J=8.2 Hz, 2H), 7.06 (t, J=7.2 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H),7.17 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H),7.65 (dd, J=1.7, 8.9 Hz 1H), 7.71 (d, J=9.2 Hz, 1H), 7.98 (d, J=1.4 Hz,1H), 8.04 (d, J=9.2 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 14.85-17.55 (bs,1H); IR (neat) 3130, 3055, 2960, 2925, 2855, 2620, 1600, 1565, 1515,1480, 1465, 1445, 1410, 1395, 1365, 1330, 1305, 1270, 1245, 1195, 1145,1105, 1050, 1015, 975, 920, 895, 825, 800, 760, 740, 700, and 665 cm⁻¹;mass spectrum [(−) ESI], m/z 634/636 (M−H)⁻;

[0166] Anal. Calcd. for C₃₆H38BrN₅O.1.25H₂O: C, 65.60; H, 6.19; N,10.62, Found: C, 65.49; H, 5.92; N, 10.29.

Example 11 {[1-Bromo-6-(1-methyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acid

[0167] Step 1

{[1-Bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acid methylester

[0168] The title compound was prepared as a solid (0.410 g, 58%) from2-(5-bromo-6-hydroxy-2-naphthyl)-3-pentyl-1H-indole using methylbromoacetate and the procedure from step 3 of Example 2; ¹H NMR(DMSO-d₆) δ 0.82 (t, J=7.0 Hz, 3H), 1.27-1.39 (m, 4H), 1.64-1.74 (m,2H), 2.93 (t, J=7.3 Hz, 2H), 3.73 (s, 3H), 5.12 (s, 2H), 7.02 (t, J=7.5Hz,1H), 7.12 (t, J=7.0 Hz,1H), 7.38 (d, J=8.0 Hz, 1H), 7.48 (d, J=9.2Hz, 1H),7.57 (d, J=7.9 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 8.03 (d, J=9.0Hz, 1H), 8.14 (d, J=1.6 Hz,1H), 8.22 (d, J=8.9 Hz,1H), 11.26 (s, 1H);mass spectrum [(+) ESI], m/z 480/482 (M+H)⁺ and [(−) ESI], m/z 478/480(M−H)⁻.

[0169] Step 2

{[1-Bromo-6-(1-methyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acid

[0170] To a stirred solution of{[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acid methylester (0.410 g, 0.853 mmol) in THF (20 mL) at 0° C. was added KOt-Bu(0.105 g, 0.938 mmol) followed by Mel (0.064 mL, 1.02 mmol). Thereaction was warmed to rt and let stir for 1 h. It appeared by TLC andMS that all the starting material was gone; however, two polar acids(one N—Me and one N—H) had been generated due to hydrolysis in thesebasic conditions. After concentration, the residue was taken up in DMF(20 mL). Added NaH (0.075 g, 60% by wt., 1.88 mmol) followed by excessMel to convert all intermediate to one acid (N—Me). After 1 h, thereaction mixture was concentrated and then diluted with EtOAc (200 mL)and 1 N HCl (20 mL). The organic layer was washed with H₂O (20 mL) andbrine (20 mL) and then dried (Na₂SO₄). After concentration, the residuewas purified by preparatory plate chromatography (10% MeOH:CHCl₃) toafford the product (0.232 g, 57%) as a yellowish-orange foamy solid,mp>73° C. (decomp.); ¹H NMR (DMSO-d₆) δ 0.73 (t, J=7.0 Hz, 3H),1.11-1.20 (m, 4H), 1.50-1.58 (m, 2H), 2.66 (t, J=7.3 Hz, 2H), 3.58 (s,3H), 4.93 (s, 2H), 7.07 (t, J=7.6 Hz, 1H), 7.19 (t, J=7.1 Hz, 1H),7.42-7.48 (m, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.68 (dd, J=1.7, 8.7 Hz, 1H),7.99 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H),11.95-14.75 (bs, 1H); IR (neat) 3050, 2955, 2925, 2850, 1725, 1670,1600, 1480, 1470, 1430, 1370, 1325, 1275, 1220, 1190, 1145, 1095, 1015,980, 925, 895, 830, 800, 765, 735, 700, and 665 cm⁻¹; mass spectrum [(+)ESI], m/z 480/482 (M+H)⁺;

[0171] Anal. Calcd. for C₂₆H₂₆BrNO₃.0.5H₂O: C, 63.81; H, 5.56; N, 2.86,Found: C, 63.67; H, 5.30; N, 2.77.

What is claimed is:
 1. A compound of Formula I:

wherein: R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of1-3 carbons, cycloalkyl of 3-5 carbon atoms, —CH₂-cycloalkyl of 3-5carbon atoms, alkanoyl of 1-3 carbons, halogen, hydroxy, aryl optionallysubstituted with from 1 to 3 groups selected from R₈, perfluoroalkyl of1-3 carbons, alkoxy of 1-3 carbons, amino, alkylamino of 1-3 carbons,dialkylamino of 1-3 carbons, perfluoroalkoxy of 1-3 carbons; R₅ ishydrogen, alkyl of 1-6 carbons, perfluoroalkyl of 1-6 carbons, arylsubstituted with R₈, alkanoyl of 1-6 carbons, aroyl optionallysubstituted with from 1 to 3 groups selected from R₈; R₆ is hydrogen,alkyl of 1-6 carbons, alkylaryl, benzyl substituted with R₈, alkanoyl of1-6 carbons, aroyl optionally substituted with from 1 to 3 groupsselected from R₈; R₇ is hydrogen, alkyl of 1-6 carbons, alkylaryl, aryloptionally substituted with from 1 to 3 groups selected from R₈; n is aninteger of 0-6; A is COOH, or an acid mimic such as tetraazole, SO₃H,PO₃H₂, tetronic acid, etc.; R₈ is hydrogen, alkyl of 1-3 carbons,cycloalkyl of 3-5 carbons, —CH₂-cycloalkyl of 3-5 carbon atoms, alkanoylof 1-3 carbons, halogen, hydroxy, perfluoroalkyl of 1-3 carbons, alkoxyof 1-3 carbons, amino, alkylamino of 1-3 carbons, dialkylamino of 1-3carbons, perfluoroalkoxy of 1-3 carbons; or a pharmaceuticallyacceptable salt or ester form thereof.
 2. A compound of claim 1 havingthe formula:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, A, n, and R₈ are as defined in claim1, or a pharmaceutically acceptable salt or ester form thereof.
 3. Acompound of claim 1 having the formula:

wherein: R₁, R₂, and R₃, are each, independently, hydrogen, alkyl of 1-3carbons, cycloalkyl of 3-5 carbons, alkanoyl of 1-3 carbons, halogen,hydroxy, aryl optionally substituted with from 1 to 3 groups selectedfrom R₆, perfluoroalkyl of 1-3 carbons, alkoxy of 1-3 carbons, amino,alkylamino of 1-3 carbons, dialkylamino of 1-3 carbons per alkyl group,perfluoroalkoxy of 1-3 carbons; R₄ is hydrogen, alkyl of 1-6 carbons,perfluoroalkyl of 1-6 carbons, aryl substituted with R₆, alkanoyl of 1-6carbons, aroyl optionally substituted with from 1 to 3 groups selectedfrom R₆; R₅ is hydrogen, alkyl of 1-6 carbons, alkylaryl, benzyloptionally substituted with from 1 to 3 groups selected from R₆,alkanoyl of 1-6 carbons, aroyl substituted with R₆; A is COOH ortetraazole; R₆ is hydrogen, alkyl of 1-3 carbons, cycloalkyl of 3-5carbons, —CH₂-cycloalkyl of 3-5 carbons, alkanoyl of 1-3 carbons,halogen, hydroxy, perfluoroalkyl of 1-3 carbons, alkoxy of 1-3 carbons,amino, alkylamino of 1-3 carbons, dialkylamino of 1-3 carbons,perfluoroalkoxy of 1-3 carbons; or a pharmaceutically acceptable salt orester form thereof.
 4. A compound of claim 1 which is1-Benzyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indoleor a pharmaceutically acceptable salt thereof.
 5. A compound of claim 1which is 6-(1-Benzyl-3-pentyl-1H-indol-2-yl)-1-bromo-2-naphthyl1H-tetraazol-5-ylmethyl ether or1-Benzyl-2-[5-bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1H-indoleor a pharmaceutically acceptable salt thereof.
 6. A compound of claim 1which is1-Methyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indoleor a pharmaceutically acceptable salt thereof.
 7. A compound of claim 1which is2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-methyl-3-pentyl-1H-indoleor 1-Bromo-6-(1-methyl-3-pentyl-1H-indol-2-yl)-2-naphthyl1H-tetraazol-5-ylmethyl ether or a pharmaceutically acceptable saltthereof.
 8. A compound of claim 1 which is1-Acetyl-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indoleor a pharmaceutically acceptable salt thereof.
 9. A compound of claim 1which is1-Acetyl-2-[5-bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1H-indoleor a pharmaceutically acceptable salt thereof.
 10. A compound of claim 1which is3-Pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-[2-(trifluoromethyl)benzyl]-1H-indoleor a pharmaceutically acceptable salt thereof.
 11. A compound of claim 1which is2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-3-pentyl-1-[2-(trifluoromethyl)benzyl]-1H-indoleor a pharmaceutically acceptable salt thereof.
 12. A compound of claim 1which is1-(4-tert-Butylbenzyl)-3-pentyl-2-[6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1H-indoleor a pharmaceutically acceptable salt thereof.
 13. A compound of claim 1which is2-[5-Bromo-6-(1H-tetraazol-5-ylmethoxy)-2-naphthyl]-1-(4-tert-butylbenzyl)-3-pentyl-1H-indoleor a pharmaceutically acceptable salt thereof.
 14. A compound of claim 1which is{[1-Bromo-6-(1-methyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acidor a pharmaceutically acceptable salt thereof.
 15. A method fortreatment of thrombosis or fibrinolytic impairment in a mammal, themethod comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of claim
 1. 16. A methodof claim 15 wherein the thrombosis or fibrinolytic impairment isassociated with formation of atherosclerotic plaques, venous andarterial thrombosis, myocardial ischemia, atrial fibrillation, deep veinthrombosis, coagulation syndromes, pulmonary fibrosis, cerebralthrombosis, thromboembolic complications of surgery or peripheralarterial occlusion.
 17. A pharmaceutical composition comprisingpharmaceutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt or ester form thereof, and apharmaceutically acceptable excipient or carrier.
 18. A method for thetreatment of stroke associated with or resulting from atrialfibrillation in a mammal, comprising administering to a mammal in needthereof a pharmaceutically effective amount of a compound of claim 1.19. A method for the treatment of deep vein thrombosis in a mammal,comprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of claim
 1. 20. A method for thetreatment of myocardial ischemia in a mammal, comprising administeringto a mammal in need thereof a pharmaceutically effective amount of acompound of claim
 1. 21. A method for the treatment of cardiovasculardisease caused by noninsulin dependent diabetes mellitus in a mammal,comprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of claim
 1. 22. A method for thetreatment of the formation of atherosclerotic plaques in a mammal,comprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of claim
 1. 23. A method for thetreatment of chronic obstructive pulmonary disease in a mammal,comprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of claim
 1. 24. A method for thetreatment of renal fibrosis in a mammal, comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof claim
 1. 25. A method for the treatment of polycystic ovary syndromein a mammal, comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of claim
 1. 26. A methodfor the treatment of Alzheimer's disease in a mammal, comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of claim
 1. 27. A method for the treatment ofcancer in a mammal, comprising administering to a mammal in need thereofa pharmaceutically effective amount of a compound of claim 1.